Bone metastasis is a common, yet serious, complication of breast cancer. Breast cancer cells that extravasate from blood vessels to the bone devastate bone quality by interacting with bone cells and disrupting the bone remodeling balance. Although exercise is often suggested as a cancer intervention strategy and mechanical loading during exercise is known to regulate bone remodeling, its role in preventing bone metastasis remains unknown. We developed a novel in vitro microfluidic tissue model to investigate the role of osteocytes in the mechanical regulation of breast cancer bone metastasis. Metastatic MDA-MB-231 breast cancer cells were cultured inside a 3D microfluidic lumen lined with human umbilical vein endothelial cells (HUVECs), which is adjacent to a channel seeded with osteocyte-like MLO-Y4 cells. Physiologically relevant oscillatory fluid flow (OFF) (1 Pa, 1 Hz) was applied to mechanically stimulate the osteocytes. Hydrogel-filled side channels in-between the two channels allowed real-time, bi-directional cellular signaling and cancer cell extravasation over 3 days. The applied OFF was capable of inducing intracellular calcium responses in osteocytes (82.3% cells responding with a 3.71 fold increase average magnitude). Both extravasation distance and percentage of extravasated side-channels were significantly reduced with mechanically stimulated osteocytes (32.4% and 53.5% of control, respectively) compared to static osteocytes (102.1% and 107.3% of control, respectively). This is the first microfluidic device that has successfully integrated stimulatory bone fluid flow, and demonstrated that mechanically stimulated osteocytes reduced breast cancer extravasation. Future work with this platform will determine the specific mechanisms involved in osteocyte mechanoregulation of breast cancer bone metastasis, as well as other types of cancer metastasis and diseases.

中文翻译：

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用于研究乳腺癌骨转移的骨细胞机械调节的微流体平台。

骨转移是乳腺癌的常见但严重的并发症。从血管扩散到骨骼的乳腺癌细胞通过与骨骼细胞相互作用并破坏骨骼重塑平衡而破坏骨骼质量。尽管通常建议将运动作为一种癌症干预策略，并且已知运动过程中的机械负荷可调节骨重塑，但其在预防骨转移中的作用仍然未知。我们开发了一种新型的体外微流体组织模型，以研究骨细胞在乳腺癌骨转移的机械调节中的作用。将MDA-MB-231转移性乳腺癌细胞培养在3D微流明内腔中，该腔内衬有人脐静脉内皮细胞（HUVEC），该通道与接种有骨细胞样MLO-Y4细胞的通道相邻。生理相关的振荡流体流量（OFF）（1 Pa，1 Hz）用于机械刺激骨细胞。两个通道之间充满水凝胶的侧通道可在3天之内进行实时双向细胞信号传导和癌细胞外渗。所施加的OFF能够诱导骨细胞中的细胞内钙应答（82.3％的细胞应答，平均幅度增加了3.71倍）。与静态骨细胞（分别为对照的102.1％和107.3％）相比，机械刺激的骨细胞（分别为对照的32.4％和53.5％）均显着降低了渗出距离和外通道的百分比。这是第一款成功整合了刺激性骨液流的微流控设备，并证明机械刺激的骨细胞减少了乳腺癌的扩散。使用该平台的未来工作将确定参与乳腺癌骨转移的骨细胞机械调节以及其他类型的癌症转移和疾病的具体机制。